Exosomal Transfer of miR-185 Is Controlled by hnRNPA2B1 and Impairs Re-endothelialization After Vascular Injury.

Yi Si,Daqiao Guo,Jianing Yue,Weiguo Fu,Chao Fang,Zhihui Dong,Baolei Guo,Xiao Tang,Zhenyu Shi,Fei Liu,Dongqing Wang

doi:10.3389/fcell.2021.619444

Abstract

Dysfunction of endothelial cells (ECs) contributes to restenosis after vascular reconstruction for patients with coronary artery disease (CAD). The intercellular communication between ECs and vascular smooth muscle cells (VSMCs) might be critical in the development of restenosis and can be mediated by exosomes carrying functional microRNAs. miR-185 is reported to be associated with atherosclerosis, whether it plays a similar role in restenosis is unknown. In this study, we observed an elevated level of extracellular miR-185 in platelet-derived growth factor (PDGF)-stimulated VSMCs. The medium from PDGF-stimulated VSMCs promoted miR-185 expression in rat aortic ECs and inhibited EC angiogenesis. PDGF-stimulated VSMCs transferred miR-185 into ECs via exosomes. Furthermore, we found that the CXCL12 gene, a target of miR-185, is essential for the angiogenic potential of ECs. Exosomes derived from miR-185 mimic transfected VSMCs attenuated re-endothelialization after vascular injury. Moreover, we show that exosome-mediated miR-185 transfer is modulated by hnRNPA2B1. We also observed that hnRNPA2B1 is up-regulated during neointima formation and hnRNPA2B1 inhibition accelerates re-endothelialization and attenuates neointima formation following carotid injury. Taken together, our results indicate that exosomal miR-185 transfer from VSMCs to ECs is controlled by hnRNPA2B1 and impairs re-endothelialization after vascular injury.

Highlights

Vascular interventions, such as angioplasty and bypass, are often performed to correct coronary artery diseases such as atherosclerosis
When endothelial cells (ECs) were exposed to media from vascular smooth muscle cells (VSMCs) stimulated with platelet-derived growth factor (PDGF)-BB (PDGF-Conditioned Media (CM)), the level of miR-185 expression increased significantly and cell proliferation was reduced
This was not observed with media from cells grown without PDGF (Basal-CM), which indicates that medium from PDGF-stimulated VSMCs could significantly influence the proliferation of ECs

Summary

Introduction

Vascular interventions, such as angioplasty and bypass, are often performed to correct coronary artery diseases such as atherosclerosis. Restenosis after vascular reconstruction is attributed to several processes, including constrictive vessel remodeling, intimal hyperplasia, and retarded re-endothelialization (Guo et al, 2014). These processes contribute to excessive matrix protein production, an overgrowth of cells and matrix in the subintimal layer, and thrombosis (Inoue et al, 2011). Vascular interventions used to correct atherosclerosis result in damage to the protective layer of endothelial cells (ECs) leaving smooth muscle cells (SMCs) exposed to the influence of cytokines and growth factors which initiate intimal growth and the constructive remodeling of restenosis (Guo et al, 2014). A method that can enable the rapid regrowth of the endothelial layer and selectively inhibit the proliferation of SMCs could prevent restenosis

Objectives

Methods

Results

Conclusion